Aging is a degenerative biological process that affects multiple organs including kidneys. The kidney function declines in the aged population. The aging-related kidney damage is an important aging process that determines the lifespan. The incidence of kidney damage increases in the aged population. For instance, the prevalence of chronic kidney disease (CKD) is higher in the aged than in the young population. Arterial stiffening, hypertension and angiogenesis are associated with CKD. CKD eventually results in multiple organ dysfunctions leading to heart failure and stroke. However, the etiology and pathogenesis of aging-related kidney damage are poorly understood. Klotho is a recently-discovered anti-aging gene. In humans, the klotho level declines in the aged population. Mutation of klotho gene shortens the lifespan while overexpression of klotho gene extends lifespan in mice. Klotho is predominately expressed in the kidney. CKD is associated with disrupted expression of renal klotho. Our new exciting preliminary data showed kidney-specific knockout of klotho gene caused interstitial fibrosis and glomerulosclerosis and impaired renal function in mice. The preliminary study also demonstrated that renal klotho expression was markedly decreased in the aging kidneys. The overall objective of this application is to determine if klotho plays a role in the maintenance of normal kidney structure and function and if klotho deficiency is involved in the pathogenesis of aging-related kidney damage (interstitial fibrosis, glomerulosclerosis, and impaired kidney function). This objective will be achieved by pursuing two coherent specific aims using a combination of several novel approaches including conditional gene knockout and in vivo tubule cell- specific and podocyte-specific gene delivery. The two specific aims are: (1) Determine if klotho deficiency causes kidney damage and related cellular and molecular mechanisms. (2) Determine if in vivo delivery of klotho gene attenuates the aging-related impairment in kidney structure and function in F344 rats. These studies will demonstrate an important role of klotho in the maintenance of normal kidney structure and function. The results will reveal novel molecular pathways that mediate the pathogenesis of aging-related kidney damage. Completion of this project may offer new insights into therapeutic strategies for aging-related kidney damage.

Public Health Relevance

Kidney disease is associated with aging. For instance, the prevalence of kidney damage is increased in the aged population. The aging-related kidney damage is an important aging process that determines the lifespan. The purpose of the proposed research is to assess if deficiency of klotho, a recently-discovered anti-aging gene, plays a role in the pathogenesis aging-related kidney damage. The results will provide novel information that klotho may protects the kidney. Completion of the project may offer a new therapeutic approach for kidney disorders. The finding will benefit the US population which has a high prevalence of kidney disease.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Research Project (R01)
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Pathobiology of Kidney Disease Study Section (PBKD)
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Rys-Sikora, Krystyna E
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University of Oklahoma Health Sciences Center
Schools of Medicine
Oklahoma City
United States
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Gao, Diansa; Zuo, Zhong; Tian, Jing et al. (2016) Activation of SIRT1 Attenuates Klotho Deficiency-Induced Arterial Stiffness and Hypertension by Enhancing AMP-Activated Protein Kinase Activity. Hypertension 68:1191-1199
Lin, Yi; Chen, Jianglei; Sun, Zhongjie (2016) Antiaging Gene Klotho Deficiency Promoted High-Fat Diet-Induced Arterial Stiffening via Inactivation of AMP-Activated Protein Kinase. Hypertension 67:564-73
Varshney, Rohan; Ali, Quaisar; Wu, Chengxiang et al. (2016) Monocrotaline-Induced Pulmonary Hypertension Involves Downregulation of Antiaging Protein Klotho and eNOS Activity. Hypertension 68:1255-1263
Chen, Kai; Zhou, Xiaoli; Sun, Zhongjie (2015) Haplodeficiency of Klotho Gene Causes Arterial Stiffening via Upregulation of Scleraxis Expression and Induction of Autophagy. Hypertension 66:1006-13
Lin, Yi; Sun, Zhongjie (2015) Antiaging Gene Klotho Attenuates Pancreatic β-Cell Apoptosis in Type 1 Diabetes. Diabetes 64:4298-311
Xu, Yuechi; Sun, Zhongjie (2015) Molecular basis of Klotho: from gene to function in aging. Endocr Rev 36:174-93
Lin, Yi; Sun, Zhongjie (2015) In vivo pancreatic β-cell-specific expression of antiaging gene Klotho: a novel approach for preserving β-cells in type 2 diabetes. Diabetes 64:1444-58
Sun, Zhongjie (2015) Aging, arterial stiffness, and hypertension. Hypertension 65:252-6
Zhou, Xiaoli; Chen, Kai; Lei, Han et al. (2015) Klotho gene deficiency causes salt-sensitive hypertension via monocyte chemotactic protein-1/CC chemokine receptor 2-mediated inflammation. J Am Soc Nephrol 26:121-32
Wang, Yuhong; Sun, Zhongjie (2014) Antiaging gene Klotho regulates endothelin-1 levels and endothelin receptor subtype B expression in kidneys of spontaneously hypertensive rats. J Hypertens 32:1629-36; discussion 1636

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